The invention concerns a method for treating tumors utilizing a combination of known oncolytic agents. The use of the agents together provides unexpectedly greater efficacy than employing the single agents alone.
Cancer chemotherapy has advanced dramatically in recent years. Many tumors can be effectively treated utilizing compounds which are either naturally occurring products or synthetic agents. Cancer chemotherapy often entails use of a combination of agents, generally as a means of providing greater therapeutic effects and reducing the toxic effects that are often encountered with the individual agents when used alone.
We have now discovered a unique combination of known oncolytic agents which exhibits a dramatic synergistic effect. The combination utilizes the agent acetyldinaline, together with either gemcitabine, capecitabine, or cisplatin. The combination is especially effective in treating patients with solid tumors, especially nonsmall cell lung cancer and other advanced solid tumors.
Acetyldinaline is 4-acetylamino-N-(2xe2x80x2-aminophenyl)-benzamide. It is also known as CI994. It is described in U.S. Pat. No. 5,137,918, which is incorporated herein by reference for its teaching of how to make acetyldinaline, how to formulate it into dosage forms, and how to use it for treating cancers such as colon cancer and adenocarcinomas. It is also described in U.S. Pat. No. 5,795,909 as a possible conjugate for cancer treatment.
Gemcitabine is the generic name assigned to 2xe2x80x2-deoxy-2xe2x80x2,2xe2x80x2-difluoro-cytidine. It is commercially available as the monohydrochloride salt, and as the xcex2-isomer. It is also known chemically as 1-(4-amino-2-oxo-1H-pyrimidin-1 -yl)-2-desoxy-2,2-difluororibose. Gemcitabine is disclosed in U.S. Pat. Nos. 4,808,614 and 5,464,826, which are incorporated herein by reference for their teaching of how to synthesize, formulate, and use gemcitabine for treating susceptible neoplasms. The commercial formulation of gemcitabine hydrochloride is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas, and is commonly used in patients previously treated with 5-fluorouracil.
Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5xe2x80x2-deoxy-5-fluorouridine (5xe2x80x2-DFUR) which is converted to 5-fluorouracil. The chemical name for capecitabine is 5xe2x80x2-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine. It is marketed in the United States as Xeloda(trademark) (Roche Laboratories). It is indicated for the treatment of patients with metastatic breast cancer and colorectal tumors. It generally is administered for 14 days, followed by a 7-day rest period during each 21-day cycle. Capecitabine is described in U.S. Pat. No. 5,472,949.
Cisplatin is the generic name for cis-diaminodichloroplatinum and is described in U.S. Pat. No. 5,562,925, which is incorporated herein by reference. Cisplatin is commercially available and is indicated for metastatic testicular and ovarian tumors, as well as advanced bladder cancer.
An object of this invention is to provide a method for treating cancers, especially advanced solid tumors. with a combination comprising acetyldinaline together with either gemcitabine, capecitabine, or cisplatin. A further object is to provide a composition comprising synergistic amounts of acetyldinaline and gemcitabine, synergistic amounts of acetyldinaline and capecitabine, and synergistic amounts of acetyldinaline and cisplatin.
This invention relates to a synergistic combination of antineoplastic agents, and to a method for treating tumors comprising administering the combination. The invention more particularly provides a composition comprising, as a first component, acetyldinaline, and as a second component, either gemcitabine, capecitabine, or cisplatin. The gemcitabine is used preferably as a pharmaceutically acceptable acid addition salt.
The compositions of this invention consist essentially of the above active ingredients, or suitable salts thereof, together with common excipients, diluents, and carriers.
A preferred composition comprises acetyldinaline, together with gemcitabine hydrochloride. Another preferred combination is acetyldinaline and cisplatin.
In a further embodiment of the invention, we provide a method for treating cancer comprising administering to an animal in need of treatment an effective amount of a combination of acetyldinaline and either cisplatin, or gemcitabine, preferably as a salt such as the hydrochloride.
A preferred method embraces treatment of solid tumors.
A further preferred method employs an antitumor amount of acetyldinaline and an effective amount of gemcitabine hydrochloride, capecitabine, or cisplatin to treat susceptible cancers, including nonsmall cell lung cancer (NSCLC), breast cancer, ovarian cancer, head and neck cancer, myelomas, prostate cancer, and pancreatic cancer.
Another embodiment of the invention is a kit comprising in one compartment a dosage of acetyldinaline, and in another compartment a dosage of gemcitabine, or a pharmaceutically acceptable salt thereof. A further embodiment is a kit comprising in one compartment a dosage of acetyldinaline, and in another compartment a dosage of capecitabine or cisplatin.